This invention relates to a series of ketolide antibacterials in the macrolide family, intermediates used in their manufacture and pharmaceutical compositions containing them. The compounds are erythromycin analogues useful in the treatment of bacterial and protozoal infections and in the treatment of other conditions involving gastric motility.
Polyketides are a family of natural products that include many compounds possessing antibiotic and other pharmacologic properties. Erythromycins are a class of macrolide antibiotics originally discovered in 1952 in the metabolic products of a strain of Streptomyces erythreus. The antibiotic occurs in various glycosylated forms, designated A, B, C and D. Since their discovery, many have worked to prepare derivatives of the molecule to improve or modify its properties. The focus of much of this work involved chemical modification of the naturally produced erythromycin molecule. This work has produced a number of derivatives including the semi-synthetic antibiotic, clarithromycin, which is 6-O-methylerythromycin. 12,11 oxycarbonyl substituted imino chemical derivatives of erythromycin are described in U.S. Pat. No. 5,635,485. However, because of the complexity of the macrolide molecule, medicinal chemistry efforts to produce derivatives have been limited by the kinds of modifications that can be made to the naturally occurring products.
Recently, work surrounding the search for modified polyketide antibiotics expanded with the discovery and isolation of the modular polyketide synthases (PKS""s); multifunctional enzymes related to fatty acid synthases, which catalyze the biosynthesis of polyketides through repeated reactions between acylthioesters to produce the polyketide chain. The entire biosynthetic gene cluster from S. erythraea has been mapped and sequenced by Donadio et al. in Industrial Microorganisms: Basic and Applied Molecular Genetics (1993) R. H. Baltz, G. D. Hegeman, and P. L. Skatrud (eds.) (Amer. Soc. Microbiol.) and the entire PKS is a modular assembly of three multifunctional proteins encoded by three separate genes. U.S. Pat. No. 5,672,491 discloses the use of cells transformed with recombinant vectors encoding a variety of PKS gene clusters, which can be used to produce a variety of active polyketides. The vectors can include native or hybrid combinations of PKS subunits, or mutants thereof, to produce a variety of polyketide compounds. Cell-free systems which effect the production of polyketides employing modular polyketide synthases are reported in WO 97/02358.
Using these techniques, production of erythromycin analogues in which C-13 bears a substitution other than the natural ethyl group have been reported, for example in WO 98/01571, WO 99/35157, WO 99/03986, and WO 97/02358. WO 98/0156 describes a hybrid modular PKS gene for varying the nature of the starter and extender units to synthesize novel polyketides, including erythromycin analogues. U. S. Pat. Nos. 5,824,513 and 6,004,787 farther describe methods to produce polyketide structures by introducing specific genetic alterations to genes encoding PKS in the EryA sequence of S. eiythraea.
The present invention is concerned with novel chemical derivatives of unnatural erythromycin analogues prepared by manipulation of the modular PKS gene clusters.

This invention is concerned with new compounds of the formula I:
wherein:
X is H, F, Cl, Br, or I;
R2 is selected from H,-COCH3 and xe2x80x94COPhenyl;
R6 is selected from H and xe2x80x940 xe2x80x94Ra where Ra is substituted or unsubstituted alkyl (C1-C10), substituted or unsubstituted alkenyl (C2-C10), or substituted or unsubstituted alkynyl(C2-C10);
R13 is selected from H,(C1-C8) alkyl, 1-alkenyl (C2-C8), l-alkynyl (C2-C8), substituted (C1-C8)alkyl, and -CH2-Rxe2x80x3 where Rxe2x80x3 is selected from H, (C1-C8) alkyl, substituted (C1-C8)alkyl, cycloalkyl, alkenyl (C2-C8), alkynyl (C2-C8), aryl, substituted-aryl, (C1-C8) alkylaryl, heterocyclo, and substituted heterocyclo; provided that R13 can not be ethyl;
R is selected from H, aryl, substituted-aryl, heterocyclo, substituted-heterocyclo, cycloalkyl, C1-C8-alkyl and C1-C8-alkenyl optionally substituted with one or more substituents selected from the group of aryl, substituted-aryl, heterocyclo, substituted-heterocyclo, hydroxy, C1-C6-alkoxy;
and the pharmaceutically acceptable salts, esters and pro-drug forms thereof
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain unsubstituted hydrocarbon groups of the specified number of carbon atoms.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocylooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloarino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2) substituted carbamyl (e.g.CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituents is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, napthyl, and biphenyl groups, each of which may be substituted.
The term xe2x80x9calkylarylxe2x80x9d or xe2x80x9caralkylxe2x80x9d refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituents may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
The term xe2x80x9ccycloalkylxe2x80x9d refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d and xe2x80x9cheterocycloxe2x80x9d refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thizaolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridinyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like. Preferred heterocyclo groups include pyridinyl, pyrazinyl, pyrimidinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, and the like.
Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl), or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like.
xe2x80x9cSubstituted heterocycloxe2x80x9d refers to heterocycle substituted by one to four substituents. Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents. Substituted-heterocyclo may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline. Substituted-heterocyclo may also be substituted with a substituted-aryl or a second substituted-heterocyclo to give for example a 4-phenylimidazol-1-yl or a 4-(pyridin-3-yl)-imidazol-1 yl.
The following substituted heterocyclo groups are particularly preferred 
The compounds of the invention are those of formula I as set forth above, as well as any stereoisomeric forms of these compounds as shown. The particular stereoisomers depicted are those resulting from the preferred method of synthesis set forth above and exemplified herein; however, by modifying the expression system for the PKS, or by altering the chirality of the diketide, or by synthetic chemical conversion, other stereoisomers may also be prepared. Additional chiral centers may be present in the substituents, such as Ra and R13. The stereoisomers may be administered as mixtures, or individual stereoisomers may be separated and utilized as is known in the art.
The compounds are expected to possess antibacterial activity against Gram positive, Gram negative, and anaerobic bacteria due to their novel structure, and are expected to be useful as broad spectrum antibacterial agents for the treatment of bacterial infections in humans and animals. These compounds are particularly expected to have antimicrobial activity against S. aureus, S. epidermidis, S. pneumoniae, S. pyogenes, enterococci, Moraxella catarrhalis and H. influenzae. These compounds are particularly expected to be useful in the treatment of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections.
Also included in the present invention are compounds useful as intermediates for producing the compounds of the present invention. Such intermediate compounds include those of the formula: 
Wherein X, R6 and R13 are as described above, and R2 is hydrogen or a hydroxyl protecting group, such as acetyl, benzoyl, or trimethylsilyl. Other intermediates included within the scope of this invention are those of the formula: 
Wherein X, R6 and R13 are as described above, and R2 is hydrogen or a hydroxyl protecting group, such as acetyl, benzoyl, or trimethylsilyl.